ABSTRACT Cancer risks associated with the use of smokeless tobacco (SLT) products worldwide vary drastically. There is a critical need to better understand SLT carcinogenesis, and which chemical constituents and/or product characteristics drive the risk of cancer development in SLT users. India has a unique tobacco burden profile and represents both an area of critical need and unique setting for such studies. Nearly one third of the population in India is using various forms of SLT, exceeding the prevalence of smoking. This is accompanied by high rates of oral and head and neck cancer (OHNC), which is strongly associated with SLT use and is a leading cause of cancer-related death in India. The goal of our proposal is to investigate the relationship between carcinogen content in SLT products and relevant exposures as well as OHNC risk in users of these products, while concurrently building capacity for a sustainable tobacco carcinogenesis research program in India. We will focus on the tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Our first aim will be to determine the variation of NNN and NNK in SLT products currently available in Mumbai including a wide range of both manufactured and cottage-made products. Our second aim will be to examine the relationship between NNN and NNK levels in SLT products and the levels of corresponding biomarkers in users of these products. In this aim, we will assess biomarkers of exposure in 300 users of SLT products with differing NNN and NNK content, as established in Aim 1. In our third aim, we will compare levels of urinary NNN and NNK biomarkers between SLT users with and without OHNC. Together, these studies we will generate important insights into the role of NNN and NNK in SLT carcinogenesis in India. While substantial work has been carried out by the Indian public health research and advocacy community to generate valuable knowledge on SLT use, perceptions, and epidemiology, biomarker-based studies of tobacco carcinogen exposure and cancer risk have never been conducted in India. Our research team is uniquely positioned to initiate this research, as it will leverage our collaborative partnership with clinicians and scientists at Tata Memorial Hospital and its affiliated Advanced Center for Training, Research and Education in Cancer in Mumbai. In addition to generating novel scientific data, this study will incorporate capacity building activities that are closely linked to the Specific Aims and include the development of analytical laboratory capacity, training of young investigators from Mumbai in tobacco research procedures, and establishment of tobacco product and biospecimen repositories for future research.